US2009137549A1PendingUtilityA1
Novel compounds useful for the treatment of degenerative & inflamatory diseases
Est. expiryNov 9, 2026(~0.3 yrs left)· nominal 20-yr term from priority
Inventors:Paul John EdwardMark Stuart ChambersChristel Jeanne Marie MenetStephen Robert FletcherRebecca E. JarvisHervé Van De PoëlAlexander SudauAlastair RaePeter Stanley Thomas
A61P 29/00C07D 487/04A61P 19/10A61P 19/02
45
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Claims
Abstract
The present invention relates to compounds that are inhibitors of PDE1A, a phosphodiesterase that is involved in the modulation of the degradation of cartilage, joint degeneration and diseases involving such degradation and/or inflammation.
Claims
exact text as granted — not AI-modified1 . A compound according to formula Ia, Ib, Ic, Id, Ie, If, Ig, or Ih:
wherein:
X represents a carbon-carbon bonded nitrogen-containing heterocycloalkyl group;
B represents substituted or unsubstituted C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;
or B represents substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkylalkyl or heterocycloalkylalkyl;
or B represents substituted or unsubstituted aralkyl, aryl or heteroaryl;
or with respect to a compound according to the formulae Ia or Ig, B further includes H, NO 2 , C 1 -C 6 alkyl, halo, —CO-aryl, —CO-heteroaryl, —CO—N(R 10 )-aryl, or CO—N(R 10 )-heteroaryl;
Y represents a bond, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
the group B—(CH 2 )n-, B—CO—, B—N(R 10 )CO—, B—SO 2 —, B—OCO—, B—N(R 10 )SO 2 —, B—Y— or B—NR 10 -D(R 9 )— is linked to X via a nitrogen atom within the X group;
D represents CH or N, with the proviso that when D represents CH, R 9 represents —NO 2 and when D represents N, R 9 represents CN;
R 1 represents H, C 1 -C 6 alkyl, (CH 2 )n-aryl, cycloalkyl or a —C 1 -C 6 alkyl-cycloalkyl group, each of which may optionally be substituted with one or more groups selected from halogen, CN, CF 3 , —NR 4 R 5 , —NR 5 COR 4 , —CONR 4 R 5 , —NR 5 SO 2 R 4 , —SO 2 NR 5 R 4 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, —COR 4 , —CO 2 R 4 , or —SO 2 R 4 ;
R 2 represents H, C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, (CH 2 )n-aryl, or a heteroaryl group, each of which may optionally be substituted with one or more groups selected from halogen, CN, —NR 4 R 5 , —NR 5 COR 4 , —CONR 4 R 5 , —NR 5 SO 2 R 4 , —SO 2 NR 5 R 4 , C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, —C 1 -C 6 haloalkoxy, —COR 4 , —CO 2 R 4 , or SO 2 R 4 ;
R 3 represents H, halogen, C 1 -C 6 alkyl, cycloalkyl, (CH 2 )n-aryl, aryl, or a heteroaryl group, each of which may optionally be substituted with one or more groups selected from halogen, CN, —NR 4 R 5 , —NR 5 COR 4 , —CONR 4 R 5 , —NR 5 SO 2 R 4 , —SO 2 NR 5 R 4 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, COR 4 , CO 2 R 4 , or SO 2 R 4 ;
R 4 represents H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, or heterocycloalkyl;
R 5 represents H, C 1 -C 6 alkyl, or cycloalkyl;
R 9 represents CN or NO 2 ;
R 10 represents H or C 1 -C 6 alkyl; and
each “n” independently represents 0, 1, 2 or 3;
or a pharmaceutically acceptable salt thereof or isotopic variants thereof, stereoisomers or tautomers thereof.
2 . A compound according to claim 1 wherein X is selected from piperidine, pyrrolidine and azetidine.
3 . A compound according to claim 1 wherein the compound is according to formulae IIa, IIb, IIc, IId, IIe, IIf, IIg, or IIh:
wherein B, Y, D, R 2 , R 3 and R 9 are as in claim 1 ; R 10 is H or Me; or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof or isotopic variants thereof, stereoisomers or tautomers thereof.
4 . (canceled)
5 . A compound according to claim 1 wherein R 2 is C 1 -C 6 alkyl, cycloalkyl, aryl, heteroaryl or heterocycloalkyl.
6 . A compound according to claim 1 wherein R 2 is Me, i-Pr, t-Bu, cyclohexyl, cyclopentyl, cyclobutyl, phenyl, 4-fluorophenyl, pyridyl or pyrrolidinyl.
7 . A compound according to claim 1 wherein R 3 is H or C 1 -C 6 alkyl.
8 . A compound according to claim 1 wherein B is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, aralkyl, heteroarylalkyl, or heterocycloalkyl.
9 . A compound according to claim 1 wherein B is n-Bu, t-Bu, Me, CF 3 , 2,2-dimethylpropyl, 3,3,3-trifluoropropyl, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, cyclohexylmethyl, benzyl, 4-fluorobenzyl, 3,4-dichlorobenzyl, alpha-methylbenzyl, piperidinyl, or tetrahydropyranyl.
10 . A compound according to claim 1 wherein B is unsubstituted or substituted aryl.
11 . A compound according to claim 1 wherein
B is phenyl unsubstituted or substituted with one or more groups selected from halogen, CN, —NO 2 , NR 4 R 5 , NR 5 COR 4 , CONR 4 R 5 , NR 5 SO 2 R 4 , SO 2 NR 5 R 4 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, heterocycloalkylalkyl, COR 4 , CO 2 R 4 , and SO 2 R 4 ; or B is phenyl substituted with substituted or unsubstituted aryl, cycloalkyl, heterocycloalkyl or heteroaryl.
12 . A compound according to claim 1 wherein
B is heteroaryl unsubstituted or substituted with one or more groups selected from halogen, CN, —NO 2 , NR 4 R 5 , NR 5 COR 4 , CONR 4 R 5 , NR 5 SO 2 R 4 , SO 2 NR 5 R 4 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, heterocycloalkylalkyl, COR 4 , CO 2 R 4 , and SO 2 R 4 ; or B is heteroaryl substituted with substituted or unsubstituted aryl, cycloalkyl, heterocycloalkyl or heteroaryl.
13 . A compound according to claim 1 wherein B is phenyl substituted with one or more groups selected from Me, Et, i-Pr, n-Bu, t-Bu, F, Cl, CF 3 , OMe, OEt, OCF 3 , OCHF 2 , CN, —NO 2 , CO 2 Me, NHAc, NH 2 , NMe 2 , COMe, NHSO 2 Me, NHSO 2 Et, and NHSO 2 —(CH 2 ) 4 -Me.
14 . A compound according to a claim 1 wherein B is phenyl substituted with piperazin-1-yl, N-methylpiperazin-1-yl, N-isopropylpiperazin-1-yl, morpholin-1-yl, piperidin-1-yl, pyrrolidin-1-yl, or morpholin-1-ylmethyl.
15 . A compound according to claim 1 wherein B is substituted or unsubstituted heteroaryl.
16 . A compound according to any one of claims 1 - 3 wherein the compound is according to formulae Ig, or IIg; and the group B—Y— is selected from
wherein each one of R 8c or R 8d is independently selected from H, halogen, CN, —NO 2 , NR 4 R 5 , NR 5 COR 4 , CONR 4 R 5 , NR 5 SO 2 R 4 , SO 2 NR 5 R 4 , COR 4 , CO 2 R 4 , and SO 2 R 4 , or
each one of R 8c or R 8d is independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, and C 1 -C 6 haloalkoxy, or
each one of R 8c or R 8d is independently selected from heterocycloalkylalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylphenyl, aryl and heteroaryl;
R 8e is selected from H, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl; or
R 8e is selected from heterocycloalkylalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylphenyl, aryl or heteroaryl; and each of subscript m1 and m2 is independently selected from 0, 1, and 2.
17 . A compound according to claim 16 wherein each of R 8c or R 8d is selected from H, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, heterocycloalkylalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylphenyl, aryl or heteroaryl.
18 . A compound according to any one of claims 1 - 3 wherein the compound is according to formulae Ig, or IIg; and the group B—Y— is selected from
19 . A compound according to claim 1 wherein the compound is according to formulae IVa, IVb, IVc or IVd:
wherein R 8a and R 8b are independently selected from H, halogen, CN, —NO 2 , NR 4 R 5 , NR 5 COR 4 , CONR 4 R 5 , NR 5 SO 2 R 4 , SO 2 NR 5 R 4 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, COR 4 , CO 2 R 4 , SO 2 R 4 , heterocycloalkylalkyl, cycloalkyl, heterocycloalkyl.
20 . A compound according to claim 19 wherein each of R 8a or R 8b is selected from H, C 1 -C 6 alkyl, halo, CN, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, amino, dialkylamino, heterocycloalkyl, and heterocycloalkylalkyl.
21 . (canceled)
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32 . (canceled)
33 . A compound according to claim 1 wherein the compound is according to formulae VIIIa, VIIIb, VIIIc or VIIId:
wherein R 8a and R 8b are independently selected from H, halogen, CN, —NO 2 , NR 4 R 5 , NR 5 COR 4 , CONR 4 R 5 , NR 5 SO 2 R 4 , SO 2 NR 5 R 4 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, COR 4 , CO 2 R 4 , SO 2 R 4 , cycloalkyl, heterocycloalkyl, heterocycloalkylalkyl heterocycloalkylphenyl, aryl or heteroaryl.
34 . A compound according to claim 33 wherein R 8a and R 8b are independently selected from H, C 1 -C 6 alkyl, halo, CN, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, amino, dialkylamino, heterocycloalkyl, and heterocycloalkylalkyl.
35 . (canceled)
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63 . (canceled)
64 . A compound according to claim 1 wherein the compound is according to formulae XXa, XXb, XXc or XXd:
wherein R 8a and R 8b are independently selected from H, CN, —NO 2 , NR 4 R 5 , NR 5 COR 4 , CONR 4 R 5 , NR 5 SO 2 R 4 , SO 2 NR 5 R 4 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, COR 4 , CO 2 R 4 , and SO 2 R 4 .
65 . A compound according to claim 64 wherein R 8a and R 8b are independently selected from H, C 1 -C 6 alkyl, halo, CN, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, amino, dialkylamino, heterocycloalkyl, and heterocycloalkylalkyl.
66 . (canceled)
67 . (canceled)
68 . A compound according to claim 64 wherein R 8a is H, Me, NMe 2 , Cl or F; and R 8b is H, Me, Cl or F.
69 . A compound according to claim 64 wherein R 8a is H; and R 8b is H, Me, Cl, F, NMe 2 , OMe, i-Pr, t-Bu, OCF 3 , CF 3 , CN, morpholin-1-yl, piperazin-1-yl, N-methylpiperazin-1-yl or N-isopropylpiperazin-1-yl.
70 . (canceled)
71 . (canceled)
72 . A compound according to claim 1 wherein the compound is according to formulae XXIVa, XXIVb, XXIVc or XXIVd:
wherein Y is substituted or unsubstituted heteroaryl; and B is selected from H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halo, —CN, NO 2 , aryl, heteroaryl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkylphenyl, and aralkyl.
73 . (canceled)
74 . A compound according to claim 72 wherein B is selected from pyridyl, pyrimidyl, pyrazinyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzthiazolyl, benz[1,3]dioxalyl, thiophenyl, pyrrolidinyl, furanyl, triazolyl, thiazolyl, imidazolyl, oxazolyl, oxadiazolyl, and tetrazolyl.
75 . A compound according to claim 72 wherein B is selected from H, Me, t-Bu, F, Cl, CF 3 , —CN, NO 2 , Ph, morpholin-1-yl, piperidin-1-yl, piperazin-1-yl, N-Me-piperazin-1-yl, N-i-Pr-piperazin-1-yl, morpholinylmethyl, piperidinylmethyl, piperazinylmethyl, N-Me-piperazinylmethyl, N-i-Pr-piperazinylmethyl, morpholinylphenyl, piperidinylphenyl, piperazinylphenyl, N-Me-piperazinylphenyl, and N-i-Pr-piperazinylphenyl.
76 . A compound according to claim 72 wherein the group B—Y— is selected from
wherein each one of R 8c or R 8d is independently selected from H, halogen, CN, —NO 2 , NR 4 R 5 , NR 5 COR 4 , CONR 4 R 5 , NR 5 SO 2 R 4 , SO 2 NR 5 R 4 , SO 2 R 4 , COR 4 , CO 2 R 4 , and SO 2 R 4 , or
each one of R 8c or R 8d is independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, and C 1 -C 6 haloalkoxy, or
each one of R 8c or R 8d is independently selected from heterocycloalkylalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylphenyl, aryl and heteroaryl;
R 8e is selected from H, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl; or
R 8e is selected from heterocycloalkylalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylphenyl, aryl or heteroaryl; and
each of subscript m1 and m2 is independently selected from 0, 1, and 2.
77 . A compound according to claim 76 wherein each of R 8c or R 8d is independently selected from H, Me, t-Bu, F, Cl, CF 3 , Ph, —CN, NO 2 , morpholin-1-yl, piperidin-1-yl, piperazin-1-yl, N-Me-piperazin-1-yl, N-i-Pr-piperazin-1-yl, morpholinylmethyl, piperidinylmethyl, piperazinylmethyl, N-Me-piperazinylmethyl, N-i-Pr-piperazinylmethyl, morpholinylphenyl, piperidinylphenyl, piperazinylphenyl, N-Me-piperazinylphenyl, and N-i-Pr-piperazinylphenyl; and each of subscript m1 and m2 is independently selected from 1 and 2.
78 . A compound according to claim 72 wherein the group B—Y— is selected from
79 . (canceled)
80 . (canceled)
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82 . (canceled)
83 . A compound according to claim 1 wherein the compound is according to formulae XXVIIIa, XXVIIIb, XXVIIIc or XXVIIId:
wherein B is selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted heteroaryl and substituted or unsubstituted aralkyl; and the group D-R 9 is N—CN or CH—NO 2 .
84 . (canceled)
85 . A compound according to claim 83 wherein B is selected from t-Bu, i-Pr, n-Bu, cyclohexyl, cyclopentyl, cyclohexylmethyl, cyclopentylmethyl, piperidinyl, and benzyl.
86 . (canceled)
87 . (canceled)
88 . A compound according to claim 1 wherein the compound is selected from:
N-(benzo[d][1,3]dioxol-5-yl)-3-(1-tert-butyl-3-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)azetidine-1-carboxamide;
3-(1-cyclohexyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-N-(4-(4-isopropylpiperazin-1-yl)phenyl)azetidine-1-carboxamide;
3-(1-cyclohexyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-N-(4-(4-methylpiperazin-1-yl)phenyl)azetidine-1-carboxamide;
3-(1-cyclohexyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-N-(3,4-dimethylphenyl)azetidine-1-carboxamide;
3-(1-cyclohexyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-N-(cyclohexylmethyl)azetidine-1-carboxamide;
3-(1-tert-butyl-3-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-N-phenylazetidine-1-carboxamide;
3-(1-cyclohexyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-N-(3-(dimethylamino)phenyl)azetidine-1-carboxamide;
N-(3-chlorophenyl)-3-(1-cyclohexyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)azetidine-1-carboxamide;
3-(1-cyclohexyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-N-(4-(dimethylamino)phenyl)azetidine-1-carboxamide;
3-(1-cyclohexyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-N-(4-morpholinophenyl)azetidine-1-carboxamide;
3-(1-cyclohexyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-N-phenylazetidine-1-carboxamide;
3-(1-tert-butyl-3-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-N-(4-fluorophenyl)azetidine-1-carboxamide;
3-(1-cyclohexyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-N-(4-methoxyphenyl)azetidine-1-carboxamide;
3-(1-cyclohexyl-3-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-N-phenylazetidine-1-carboxamide;
3-(1-tert-butyl-3-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-N-cyclohexylazetidine-1-carboxamide;
3-(1-tert-butyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-N-(4-fluorophenyl)azetidine-1-carboxamide;
3-(1-tert-butyl-3-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-N-(4-fluorobenzyl)azetidine-1-carboxamide;
3-(1-cyclohexyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-N-(4-isopropylphenyl)azetidine-1-carboxamide;
3-(1-cyclohexyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-N-(4-fluorophenyl)azetidine-1-carboxamide;
3-(1-cyclohexyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-N-(3,4-difluorophenyl)azetidine-1-carboxamide;
3-(1-cyclohexyl-3-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-N-(4-fluorophenyl)azetidine-1-carboxamide;
N-benzyl-3-(1-tert-butyl-3-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)azetidine-1-carboxamide;
N-cyclohexyl-3-(1-cyclohexyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)azetidine-1-carboxamide;
N-benzyl-3-(1-cyclohexyl-3-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)azetidine-1-carboxamide;
3-(1-cyclohexyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-N-(4-(trifluoromethoxy)phenyl)azetidine-1-carboxamide;
tert-butyl 3-(3-(1-cyclohexyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)azetidine-1-carboxamido)piperidine-1-carboxylate;
3-(1-cyclohexyl-3-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-N-(4-fluorobenzyl)azetidine-1-carboxamide;
3-(1-cyclohexyl-3-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-N-(4-methoxybenzyl)azetidine-1-carboxamide;
N-(2-(difluoromethoxy)phenyl)-3-(1-(4-fluorophenyl)-3-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)azetidine-1-carboxamide;
3-(1-cyclohexyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-N-(4-fluorobenzyl)azetidine-1-carboxamide;
N-benzyl-3-(1-cyclohexyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)azetidine-1-carboxamide;
3-(1-cyclohexyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-N-cyclopentylazetidine-1-carboxamide;
N-(4-cyanophenyl)-3-(1-cyclohexyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)azetidine-1-carboxamide;
N-butyl-3-(1-cyclohexyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)azetidine-1-carboxamide;
3-(1-cyclohexyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-N-(4-(trifluoromethyl)phenyl)azetidine-1-carboxamide;
3-(1-cyclohexyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-N-(3,4-dichlorobenzyl)azetidine-1-carboxamide;
N-tert-butyl-3-(1-cyclohexyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)azetidine-1-carboxamide;
3-(1-cyclohexyl-3-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-N-(3,4-dichlorobenzyl)azetidine-1-carboxamide;
3-(1-cyclohexyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)azetidine-1-carboxamide;
tert-butyl 4-(3-(1-cyclohexyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)azetidine-1-carboxamido)piperidine-1-carboxylate;
(S)-3-(1-cyclohexyl-3-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-N-(1-phenylethyl)azetidine-1-carboxamide; and
3-(1-cyclohexyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-N-(3,3,3-trifluoropropyl)azetidine-1-carboxamide;
or a pharmaceutically acceptable salt thereof, and isotopic variants thereof, stereoisomers and tautomers thereof.
89 . (canceled)
90 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound according to claim 1 .
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97 . A method of treatment or prevention of diseases associated with bone and/or cartilage degradation, which comprises administering to a subject in need thereof, a therapeutically effective amount of a compound according to claim 1 .
98 . A method of treatment or prevention of rheumatoid arthritis, which comprises administering to a subject in need thereof, a therapeutically effective amount of a compound according to claim 1 .
99 . A method of treatment or prevention of osteoarthritis, which comprises administering to a subject in need thereof, a therapeutically effective amount of a compound according to claim 1 .Join the waitlist — get patent alerts
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